Glucocorticoids are important steroids for intermediary metabolism, immune, musculosceletal, connective tissue and brain function. Their importance is plainly evident in patients having glucocorticoid deficiency. Prior to the availability of replacement therapy their one-year survival rate was less than 20%. The production and secretion of the most important glucocorticoid, cortisol, is governed by a complex and highly efficient system that includes the hypothalamus, pituitary and the adrenal glands i.e. hypothalamic-pituitary-adrenal axis. Cortisol secretion is regulated by the suprachiasmatic nucleus of the hypothalamus into a circadian release rhythm. The timing is synchronized with the solar day by dark-light shifts, which normally reflect the habitual sleep-wake pattern. Therefore in healthy persons, the cortisol secretion has a 24-hour circadian pattern with peak serum levels in the early morning, 3-6 hours after onset of sleep, and nadir levels around midnight. Physical and psychological stressors also activate cortisol secretion. Under stress conditions such as surgery, fever, physical activity, or mental stress, serum cortisol concentration is increased by the release of cortico-releasing hormone (CRH) from the hypothalamus, which stimulates synthesis and secretion of adrenocorticotropin (ACTH) in the pituitary, which makes the adrenal cortex respond with increased production and secretion of cortisol. The estimated number of secretory bursts of ACTH is 40 per 24 h. Approximately 15 min after each burst of ACTH there is a surge of cortisol released into the circulation.
Glucocorticoid deficiency has a variety of causes. The incidence of each individual disorder associated with glucocorticoid deficiency is low. These disorders, however, often occur in children and young adults, and individuals suffering from such conditions will have to depend on substitution therapy for the rest of their lives. The prevalence of these chronic disorders is therefore significant. The substitution therapy that can be provided today may be regarded as unphysiological in terms of the plasma concentration profile and the release profile of the glucocorticoids from the preparations used.
The onset of adrenocortical insufficiency may vary from insidious to an acute life-threatening situation with severe salt and water deficit, which leads to shock and death if not treated adequately. Frequently reported symptoms associated with more insidious adrenocortical insufficiency are asthenia, weakness, lethargy, easy fatigability, nervousness, irritability, apathy, dizziness, headache, myalgia, anorexia, weight loss, nausea, vomiting, and diarrhoea. A recent review by Arit et al. (Lancet (2003) 361, 1881-1893) inter alia describes conditions leading to adrenal insufficiency and is hereby incorporated by reference. Three general types of adrenocortical insufficiency can be discerned. Primary adrenocortical insufficiency is usually referred to as Addison's disease. In this disorder, the adrenal cortex is affected meaning that the function of the three hormone systems produced in the adrenal cortex is impaired. The consequence of Addison's disease is therefore insufficient production and secretion of cortisol, adrenal androgens and mineralocorticoids (aldosterone).
Secondary or central adrenocortical insufficiency is mainly caused by tumours in the hypothalamic-pituitary area. The problem and the treatment considerations of secondary glucocorticoid deficiency are, however, similar to those in patients with primary adrenal failure.
Tertiary adrenal insufficiency is probably the most common cause of glucocorticoid deficiency. It is a result of long term, high dose glucocorticoid therapy as a part of treatment in patients with pulmonary diseases, autoimmune and inflammatory diseases and in the treatment of various malignancies, which results in the suppression of endogenous secretion of adrenal glucocorticoids. Tertiary adrenal insufficiency may last from a few weeks to a year.
In most cases of primary and secondary adrenal insufficiency replacement therapy with glucocorticoids is a life long treatment. The aim of glucocorticoid replacement therapy is to mimic the circadian serum cortisol profile, respond to the increased cortisol need during physical and psychological stimuli and obtain normal well-being, metabolism and long-term outcome. Both during childhood and adulthood, under-treatment can lead to malaise, postural hypotension, poor response to stress and electrolyte disturbances and even acute adrenal crisis. In childhood, an appropriate replacement dose of glucocorticoids is crucial to avoid growth suppression and reduced final height potential that are associated with glucocorticoid excess. In adults, excessive glucocorticoid replacement may induce glucose intolerance, abdominal obesity, hyper-tension, protein catabolism and osteoporosis.
Currently, the usual replacement regimen for cortisol in adults consists of 15-30 mg of hydrocortisone administered in two or three doses over a day. Synthetic glucocorticoids, such as dexamethasone or prednisolone of a longer duration are also used in replacement therapy. These synthetic compounds are, however, more potent that hydrocortisone. Their use thus increases the risk of over-treatment and adverse effects.
The estimated daily cortisol production rate in normal subjects varies between 4-15 mg/m2 per day or, according to more recent studies between 9 and 11 mg/m2 per day. In order to describe the 24-hour variation in serum cortisol levels adequately, one study divided the day into four phases. Phase 1 is a 6-hours period of minimal secretory activity 4 h before and 2 h after onset of sleep. Phase 2 refers to the 3rd to 5th hours of sleep when there is a preliminary nocturnal secretory episode. Phase 3 is a 4-hour main secretory phase during the last 3 h of sleep and the first hour after wakening. Phase 4 is an 11-hour phase of intermittent secretory activity when there is a slow decline in serum levels of cortisol.
In a study by Mah et al. (Clinical Endocrinology (2004) 61, 367-375) the circadian rhythm of serum cortisol of normal subjects is described. Peak levels of about 400-800 mmol/l, about 150-300 mmol/l and about 150 mmol/l are observed at about 6 am, 2 pm and 9 pm, respectively, and the lowest level is about midnight. In this study it is observed that the endogenous cortisol levels reach their highest levels within 30 minutes after wake-up. In order to mimic the circadian rhythm, Mah et al. recommend a thrice-daily treatment regimen of hydrocortisone, the first dose taken in the fasted state and delaying the breakfast 1-3 hours and the other two doses taken 15-60 min before food. A trice-daily regimen is also recommended in a recent review by Czock et al. (Clin. Pharmacokinet (2005) 44, 61-98) due to the short half-life of hydrocortisone, and for prednisolone a twice-daily regimen is preferred over a once-daily regimen.
A twice-daily administration of hydrocortisone with two-thirds of the total dose administered in the morning and the remainder in the afternoon (4-6 pm), results in a very low serum level of cortisol in late afternoon (3-6 pm) and late night/early morning (3-8 am). In this administration regime peak serum cortisol levels are found to surpass those observed in healthy subjects. Furthermore, patients on long term glucocorticoid replacement therapy more frequently have a low bone mineral density and an abnormal glucose tolerance.
Another problem of the need for two or three administrations per day under current treatment is that it results in non-compliance, either missing a dose or missing the timing of a dose, which leads to similar sub-optimal outcomes, especially over long periods of time. The present inventors address this problem by the once-daily aspect of the invention.
WO 02/072033 (Penwest Pharmaceuticals Co) describes a chronotherapeutic dosage form containing glucocorticosteroid. The dosage form is designed to release the glucocorticosteroid after a lag time of 2-18 hours after administration. The dosage form is intended to be administered before sleep and to start the release during sleep in order to provide the required serum level at wake-up time. However, due to large variations within and between individuals of the transit time in the various parts of the gastrointestinal tract, it is contemplated that it is difficult to reach the desired cortisol serum level at the desired point in time before wakening up.
Accordingly, there is a need of improved therapies for the treatment of a glucocorticoid deficiency disorder, which is more adapted to mimic the circadian cortisol serum profile. To this end, there is a need for an improved pharmaceutical composition or kit that enables a faster on-set of action and a longer-lasting effect compared to commercially available compositions. Furthermore, such kits or compositions may lead to better patient compliance as the dose frequency can be reduced to once daily.